9-4576636-C-G

Variant names:

• chr9-4576636-C-G
• rs773968205
• NM_004170.6:c.1066C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004170.6(SLC1A1):​c.1066C>G​(p.Arg356Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC1A1 NM_004170.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• Publications: 0 publications found

Genes affected

SLC1A1 (HGNC:10939): (solute carrier family 1 member 1) This gene encodes a member of the high-affinity glutamate transporters that play an essential role in transporting glutamate across plasma membranes. In brain, these transporters are crucial in terminating the postsynaptic action of the neurotransmitter glutamate, and in maintaining extracellular glutamate concentrations below neurotoxic levels. This transporter also transports aspartate, and mutations in this gene are thought to cause dicarboxylicamino aciduria, also known as glutamate-aspartate transport defect. [provided by RefSeq, Mar 2010]

SPATA6L (HGNC:25472): (spermatogenesis associated 6 like) Predicted to enable myosin light chain binding activity. Predicted to be involved in spermatogenesis. Predicted to be located in sperm connecting piece. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004170.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A1	NM_004170.6	MANE Select	c.1066C>G	p.Arg356Gly	missense	Exon 10 of 12	NP_004161.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A1	ENST00000262352.8	TSL:1 MANE Select	c.1066C>G	p.Arg356Gly	missense	Exon 10 of 12	ENSP00000262352.3
	SLC1A1	ENST00000422398.1	TSL:4	c.352C>G	p.Arg118Gly	missense	Exon 4 of 5	ENSP00000414620.1
	SPATA6L	ENST00000485616.5	TSL:2	n.*782-22248G>C		intron	N/A	ENSP00000420003.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461794 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111918

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.51	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.66		Gain of ubiquitination at K352 (P = 0.0619)
MVP		0.55
MPC		0.25
ClinPred		0.99	D
GERP RS		0.15
Varity_R		0.71
gMVP		0.97
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs773968205; hg19: chr9-4576636;